20110917-血脂领域的热点问题-廖玉华(1)

ICUHInstituteofCardiologyUnionHospital2011血脂领域的热点问题华中科技大学协和医院心血管病研究所生物靶向治疗教育部重点实验室廖玉华ICUHInstituteofCardiologyUnionHospitalICUHInstituteofCardiologyUnionHospital1.AS发病机理：是LDL惟一作用？还是LDL和单核/巨噬细胞双刃剑？2.强化降脂他汀的安全性问题？3.ACS-PCI术前负荷剂量他汀治疗：是强化降脂？还是抗炎作用？血脂领域的热点问题ICUHInstituteofCardiologyUnionHospitalAS发生两必备因素：LDL和单核/巨噬细胞（Nature2008）•内皮功能受损是AS启动环节•LDL-C是AS重要致病因子•炎症反应参与AS致病全过程ICUHInstituteofCardiologyUnionHospital为什么LDL具有致炎症作用？LDLHDLTRIGLYCERIDECHOLESTERYLESTERSPHOSPHOLIPIDSFREECHOLESTEROLPROTEINS5-6%22-26%35-45%6-15%22-25%-7%10-20%25%-5%-45%20-25nm8-13nm低密度脂蛋白高密度脂蛋白甘油三酯胆固醇脂磷酯游离胆固醇蛋白质胆固醇磷脂载脂蛋白胆固醇酯甘油三酯ECB-100富含胆固醇的脂蛋白（LDL/HDL)20~123nm蛋白颗粒具有较好的免疫源性ICUHInstituteofCardiologyUnionHospital目标100mg/dLLDL-C水平(mg/dL)*危险度很高的患者以及高TG、非HDL-C＜100mg/dL的患者的治疗选择;**治疗选择:70mg/dL=1.8mmol/L;100mg/dL=2.6mmol/L;130mg/dL=3.4mmol/L;160mg/dL=4.1mmol/L或最佳水平70mg/dL*10070130160190高危险度CHD或CHD等危症(10年危险度＞20%)中高危险度≥2种危险因素(10年危险度10-20%)中危险度低危险度≥2种危险因素(10年危险度＜10%)＜2种危险因素目标130mg/dL或最佳水平100mg/dL**目标130mg/dL目标160mg/dLCirculation2004;110:227-39NCEPATPIII推荐的LDL-C新目标(2004更新版)LDL-C在什么水平LDL开始致动脉粥样硬化？？？？？ICUHInstituteofCardiologyUnionHospitalRidkerPM,NEnglJMed2008;359(21):2195-207.既往无CAD病史男性≥50岁女性≥60岁LDL-C130mg/dLCRP≥2.0mg/L他汀降低LDL-C和抗炎症(降hs-CRP)对于减少心血管事件均发挥重要作用LDL-C100～60mg/mLhs-CRP2mg/mLICUHInstituteofCardiologyUnionHospitalLDL-C108mg/mLhs-CRP3mg/mLLDL-C60mg/mLhs-CRP2mg/mLICUHInstituteofCardiologyUnionHospitalCholesteroldolicholsubiquinonesacetylCoAHMGCoAmevalonicacidmevalonatepyrophosphateisopentenylpyrophosphategeranylpyrophosphatefarnesylpyrophosphatesqualeneSqualenesynthaseHMGCoAsynthaseHMGCoAreductaseRegulatingpacemakerenzymeMECHANISMOFACTION.INHIBITIONOFCHOLESTEROLSYNTHESIS他汀作用靶点ICUHInstituteofCardiologyUnionHospital9体外实验阿托伐他汀抑制Th1细胞反应他汀抑制Th1效应能够被甲羟戊酸阻断05101520253000.313Atorvastatin(μmol/L)IFN-γ-producingTcells(%)A012345600.313Atorvastatin(μmol/L)IL-4-producingTcells(%)B*P0.05vs.culturedwithoutatorvastatingroup#P0.05vs.culturedwithatorvastatin(3μmol/L)groupChengX,LiaoYH,etal.Circulation.2004;110(17)SupplementIII:696-697051015202500.313A+MAtorvastatinIFN-γ-producingTcells(%)***#ATh100.511.522.533.500.313A+MAtorvastatinIL-4-producingTcells(%)BTh2ICUHInstituteofCardiologyUnionHospitalLDL-C作为治疗目标的推荐I-A：极高危人群LDL-C1.8mmol/LApoB80mg/dLIIa-A：高危人群LDL-C2.5mmol/LApoB100mg/dLIIa-C：中危人群LDL-C3.0mmol/LEuropeanHeartJournal(2011)32,1769–18182011ESC/EAS血脂异常管理指南ICUHInstituteofCardiologyUnionHospitalLDL和HDL代谢与动脉粥样硬化形成apoA-1NEnglJMed2007;356:1304-1316CEPTLPL=脂蛋白脂肪酶；CE=胆固醇脂;FC=游离胆固醇;PL=胰脂酶，CETP=胆固醇脂转移蛋白胆固醇逆向转运：LDL-C与HDL-C治疗策略研究ICUHInstituteofCardiologyUnionHospitalBaselineCharacteristicsofthe208StudyPatientsWhoCompletedthe14-MonthAssessmentofCarotidIntima–MediaThicknessUICUnionInstituteofCardiologyARBITER6-HALTSICUHInstituteofCardiologyUnionHospitalResults:LipidConcentrationsNiacinNiacin•Niacin:HDLincreasedby18.4%to50mgperP0.001EzetimibeP=0.01Ezetimibedeciliter•↓LDLandTG•Ezetimibe:LDLNiacindecreasedby19.2%,to66mgperdeciliterP=0.01EzetimibeP=0.001EzetimibeNiacinΔLDL-CΔHDL-CΔTG(median)Ezetimibe−17.6±20.1mg/dL−2.8±5.7mg/dL-9mg/dLNiacin−10.0±24.5mg/dL+7.5±9.2mg/dL-36mg/dLARBITER6-HALTSICUHInstituteofCardiologyUnionHospitalResults:PrimaryEndpointBetween-groupChangeinCarotidIntima-MediaThickness•Niacinwassuperiortoezetimibefortheprimaryendpointofthebetweengroupdifferenceincarotidintima-mediathickness.•P=0.003•GLMforrepeatedmeasuresARBITER6-HALTSICUHInstituteofCardiologyUnionHospitalResults:MajorCardiovascularEventsMajoradversecardiovasculareventsoccurredatasignificantlylowerincidenceintheniacin(2/160patients[1.2%]vs.theezetimibegroup(9/165patients[5.5%])•Chi-squarep=0.04;Log-rankp=0.047ARBITER6-HALTSICUHInstituteofCardiologyUnionHospitalARBITER6HALTS试验的意义依折麦布组LDL-C下降19.2%,降到66mg/dl（1.7mmol/L,P0.001)，HDL-C下降5%，CIMT没有显著变化烟酸组LDL-C下降12%，HDL-C升高18.4%，（升到50mg/dl，P0.001），CIMT显著降低ARBITER6验证了LDL-C与HDL-C的作用：单纯降低LDL-C不能使斑块消退适度降低LDL-C和升高HDL-C使斑块消退ICUHInstituteofCardiologyUnionHospitalICUHInstituteofCardiologyUnionHospitalHDL代谢途径与胆固醇逆转运Cla-1/SR-BI受体外周细胞Preb-HDLABCA-1受体乳糜微粒残体乳糜微粒肠道肝脏合成肝脏肝脏分解LPL游离胆固醇ApoA-I肠道合成ApoA-IIHDLVLDLLDLTGCETP①②③ICUHInstituteofCardiologyUnionHospital临床试验药物最终LDL-CHDL-C变化Apo-A1变化PAVP值REVERSAL普伐他汀40mg/d110mg/dL+5.6%—+1.6%p0.001阿托伐他汀80mg/d79mg/dL+2.9%—+0.2%#-0.4%p=0.18p=0.98PERISCOPE吡格列酮96mg/dL+16%—-0.16%p=0.44APPROACH罗格列酮94mg/dL+14.6%—-0.21%p=0.53ASTEROID瑞舒伐他汀40mg/d60mg/dL+14.7%+8.9%-0.79%P0.001COSMOS瑞舒伐他汀16.9mg/d82mg/dL+19.8%+17.0%#-5.1%P0.0001注：—代表没有公布数据，#代表斑块总体积变化(TAV)，PAV代表粥样斑块体积百分比，+代表增加，-代表减少廖玉华诸骏仁.临床心血管病杂志2010，26（1）：1-3ICUHInstituteofCardiologyUnionHospital冠脉斑块体积百分比与血脂变化的对应比较冠脉粥样斑块的逆转与LDL-C降低和HDL-C+apoA-Ⅰ升高有关ICUHInstituteofCardiologyUnionHospital血脂管理和斑块逆转常规降脂—强化降脂—适度调脂改善生活方式标准治疗强化治疗LDL-C100mg/dLLDL-C70mg/dL适度调脂适度调脂逆转斑块减少胆固醇流入斑块：LDL-C-44%(80-95mg/dl)增加胆固醇流出斑块：ApoA1+9%(150mg/dl)HDL-C+15%(45-55mg/dl)廖玉华诸骏仁.临床心血管病杂志2010，26（1）：1-3ICUHInstituteofCardiologyUnionHospitalICUHInstituteofCardiologyUnionHospital1.AS发病机理：是LDL惟一作用？还是LDL和单核/巨噬细胞双刃剑？——他汀发挥调脂和抗炎作用，——逆转斑块的胆固醇转运主要是HDL2.强化降脂他汀的安全性问题？3.ACS-PCI术前负荷剂量他汀治疗：是强化降脂？还是抗炎作用？血脂领域的热点问题ICUHInstituteofCar